Nervous system function is critically dependent on the pattern of connectivity that is defined during development, modified by experience and perturbed in disease. We will focus on three specific aspects of axon growth cone signal transduction in the proposed studies. The first aim is to provide a comprehensive understanding of Sema3 signaling. Because of the central role of class 3 Semaphores as growth-cone-collapsing agents and of the unique nature of the Plexin cytoplasmic domain, this work will contribute in a central way to understanding axon guidance. By exploring RGM/Neogenin signaling in the second aim, the basis of action for a recently defined class of axon guidance factor and the signaling specificity of Neogenin versus DCC will be defined. The understanding of basic axon guidance mechanisms derived from Aims 1 and 2 lays the groundwork for ongoing studies of axonal misdirection and failed growth in human disease states. Any attempts at clinical intervention must draw on such a fund of knowledge. In the third aim, a specific human disease that may be linked to altered axon guidance is considered. Such work may provide an understanding of how genetically determined alterations in axonal connectivity can lead to human disease. While LGI1 mutation in ADPEAF is not a common form of epilepsy, it is likely that parallel pathways are causative in a larger number of sporadic cases of epilepsy. Together these studies will provide novel molecular insights into how nervous system connectivity is assembled or misassembled during development. These findings will have implications for the understanding developmental disorders of the brain arid will aid in the design of therapies based on axonal growth and regeneration